Shedding Light on a Cornucopia of Breast Tumor Biomarker Assays

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Just because an assay is available does not mean it should be ordered. I have found a very simple rule that works quite well every time: Order a test only when it is useful or helpful.

—Melanie Royce, MD, PhD

As our understanding of the complexities of breast cancer expands, so does our treatment armamentarium—and along with it the range of factors that must be included in our treatment decisions. Gone is the simple algorithm of adjuvant chemotherapy for almost every patient with a ≥ 2-cm tumor, except for the very elderly or very frail, and/or 5 years of endocrine therapy for practically all patients with hormone receptor–positive disease with either tamoxifen or aromatase inhibitor in pre- and postmenopausal women, respectively. Today, decisions for systemic therapy for early-stage invasive breast cancer are based not only on the usual clinical and histologic tumor characteristics, but also on breast cancer subtype. Increasingly, breast tumor biomarker assay(s) are being added into the decision algorithm, supposedly to make risk stratification more precise and to direct the clinician toward a more personalized treatment that is most appropriate for the patient.

Melanie Royce, MD, PhD

Melanie Royce, MD, PhD

Given the available breast tumor biomarker assays, the question is which ones deliver on their promise? As we seek an answer to this question, equally important is to understand the appropriate setting in which to order a biomarker assay. Even when used appropriately, assay results can sometimes be confusing and disastrously misleading when assays are ordered inappropriately. This is why guidelines become immensely helpful.

In the ASCO clinical practice guideline recently reported by Harris et al1 and summarized in this issue of The ASCO Post, the authors distilled the available evidence from the literature and provided bottom-line recommendations for clinicians wherein the decision algorithm a biomarker assay may (or may not) be useful and in which specific settings of early-stage invasive breast cancer is (or is not) applicable. The article provides a comprehensive but concise account of how the recommendations were derived. The recommendations are presented succinctly and clearly and include an assessment of the quality of the evidence and the strength of the recommendation.

Clinicians Beware

One limitation pointed out by the authors, which is not necessarily to the guidelines but to the available literature, is that no studies meeting guideline criteria for clinical utility were found to guide the choice of specific treatment regimens. So, clinicians beware when you justify your choice of chemotherapy on the basis of a particular recurrence score: There is no basis for it!

As we move toward personalized/precision medicine, the clinician must be careful where he or she applies the “tools of the trade.” No matter the advances in tumor biomarker assays, there is no substitute for critical decision making. In other words, just because an assay is available does not mean it should be ordered. I have found a very simple rule that works quite well every time: Order a test only when it is useful or helpful. This may be simple common sense, but I am always amazed at the times I come across assay results and am unable to discern why the assay was ordered in the first place.

Despite the cornucopia of available breast tumor biomarker assays, only Oncotype DX, EndoPredict, PAM50 Risk of Recurrence Score, uPA/PAI-1 and Breast Cancer Index were recommended for use, albeit with varying levels of Expert Panel confidence. Only Oncotype DX and PAM50 Risk of Recurrence Score met the combined merit of high-quality evidence and strong recommendation as stand-alone tests to guide decisions on adjuvant systemic chemotherapy in estrogen receptor–positive, HER2-negative, invasive breast cancer in node-negative disease. Oncotype DX or any other biomarker was not, however, recommended to guide treatment of node-positive disease; results of the RxPONDER trial2 are awaited. This is an important caveat in the current guidelines and an arena with a fast-moving target.

If a patient has estrogen receptor/progesterone receptor–positive, HER2-negative (node-negative) breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or IHC4) should not be used to guide decisions on extended endocrine therapy.

Several biomarker assays are being studied in randomized, prospective trials, the results of which may influence their future use. Some of these studies should be reported in the not-so-distant future. For instance, the MINDACT study3 was presented at the recent American Association for Cancer Research (AACR) Annual Meeting and likely will be published soon. These results could change the recommendations for MammaPrint.

Ripple Effect of Prior Oversight

Another crucial limitation of the guideline is that it provides no information on the clinical utility of the biomarker assays across different racial/ethnic backgrounds. This is not an oversight of the authors; their search simply did not show such information in the literature. Once again, the most disadvantaged populations who typically have the worst outcomes are left behind from the advances of the era, another ripple effect of previous oversight. If minorities had been actively recruited into clinical trials in the past, we would not be lamenting this today. It is time to include them in the “mainstream,” for we cannot anticipate what future ripples with far bigger consequences we may continue to encounter. ■

Dr. Royce is Professor in the Department of Internal Medicine at the University of New Mexico Comprehensive Cancer Center, Albuquerque.

Disclosure: Dr. Royce reported no potential conflicts of interest.


1. Harris LN, et al: J Clin Oncol 34:1134-1150, 2016.

2. U.S. National Institutes of Health: Available at Accessed April 21, 2016.

3. U.S. National Institutes of Health: Available at Accessed April 21, 2016.

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